ArticlePloS one2015
High-Throughput Ligand Discovery Reveals a Sitewise Gradient of Diversity in Broadly Evolved Hydrophilic Fibronectin Domains.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
39 citing papers in PubMed.
- Engineered B7-H3 Binding in Modular Gp2 Miniproteins.Biotechnology and bioengineering · 2026Article
- High-Efficiency Transformation of Integrative Libraries Under Zeocin Selection in Pichia pastoris.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Utilizing Engineered Monobodies for the Electrochemical Quantification of Lysozyme.Analytical chemistry · 2025Article
- Development of a Mesothelin-Binding Engineered Scaffold Protein as a Theranostic for Pleural Mesothelioma.Bioconjugate chemistry · 2025Article
- VesicleVoyager: In Vivo Selection of Surface Displayed Proteins That Direct Extracellular Vesicles to Tissue-Specific Targets.Journal of extracellular vesicles · 2025Article
- Computational modeling and experimental validation of the interaction between tumor biomarker mesothelin and an engineered targeting protein with therapeutic activity.Protein science : a publication of the Protein Society · 2025Article
- Engineering Affibody Binders to Death Receptor 5 and Tumor Necrosis Factor Receptor 1 With Improved Stability.Biotechnology and bioengineering · 2025Article
- Design, Construction, and Validation of a Yeast-Displayed Chemically Expanded Antibody Library.ACS synthetic biology · 2025Article
- Molecular Determinants of Affinity and Isoform Selectivity in Protein─Small Molecule Hybrid Inhibitors of Carbonic Anhydrase.Bioconjugate chemistry · 2025Article
- Enzyme-substrate co-display on yeast empowers engineering of tobacco etch virus protease activity.Protein engineering, design & selection : PEDS · 2025Article
- Design, Construction, and Validation of a Yeast-Displayed Chemically Expanded Antibody Library.bioRxiv : the preprint server for biology · 2024Article
- Sequence-developability mapping of affibody and fibronectin paratopes via library-scale variant characterization.Protein engineering, design & selection : PEDS · 2024Article
- Article
- Determinants of Developability and Evolvability of Synthetic Miniproteins as Ligand Scaffolds.Journal of molecular biology · 2023Article
- Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds.ACS synthetic biology · 2023Article
- Protein Engineering and High-Throughput Screening by Yeast Surface Display: Survey of Current Methods.Small science · 2023Article
- Position-Specific Enrichment Ratio Matrix scores predict antibody variant properties from deep sequencing data.Bioinformatics (Oxford, England) · 2023Article
- Protein engineering via sequence-performance mapping.Cell systems · 2023Review
- Design of an artificial phage-display library based on a new scaffold improved for average stability of the randomized proteins.Scientific reports · 2023Article
- Engineered protein-small molecule conjugates empower selective enzyme inhibition.Cell chemical biology · 2022Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Discovering new binding function via a combinatorial library in small protein scaffolds requires balance between appropriate mutations to introduce favorable intermolecular interactions while maintaining intramolecular integrity. Sitewise constraints exist in a non-spatial gradient from diverse to conserved in evolved antibody repertoires; yet non-antibody scaffolds generally do not implement this strategy in combinatorial libraries. Despite the fact that biased amino acid distributions, typically elevated in tyrosine, serine, and glycine, have gained wider use in synthetic scaffolds, these distributions are still predominantly applied uniformly to diversified sites. While select sites in fibronectin domains and DARPins have shown benefit from sitewise designs, they have not been deeply evaluated. Inspired by this disparity between diversity distributions in natural libraries and synthetic scaffold libraries, we hypothesized that binders resulting from discovery and evolution would exhibit a non-spatial, sitewise gradient of amino acid diversity. To identify sitewise diversities consistent with efficient evolution in the context of a hydrophilic fibronectin domain, >105 binders to six targets were evolved and sequenced. Evolutionarily favorable amino acid distributions at 25 sites reveal Shannon entropies (range: 0.3-3.9; median: 2.1; standard deviation: 1.1) supporting the diversity gradient hypothesis. Sitewise constraints in evolved sequences are consistent with complementarity, stability, and consensus biases. Implementation of sitewise constrained diversity enables direct selection of nanomolar affinity binders validating an efficient strategy to balance inter- and intra-molecular interaction demands at each site.
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